The Role of Neurotransmitters in Body Weight Regulation
Explore the ScienceObesity represents one of the most complex health challenges of our time, with a global prevalence that has tripled since 1975 and now affects approximately 13% of the world's adult population 1 .
For decades, we considered excess weight primarily as a matter of willpower or calorie balance. Emerging scientific reality reveals an infinitely more sophisticated picture: an intricate neurochemical dialogue involving a network of neurotransmitters and brain circuits that constantly influence our food choices, our metabolism, and our relationship with food.
Approximately 90-95% of the body's serotonin is produced peripherally, mainly in the gut, while a smaller percentage (less than 1%) acts centrally as a neurotransmitter 2 .
Among the protagonists of this complex biochemical conversation are two well-known molecules: serotonin and dopamine. These neurotransmitters, known for their role in regulating mood and pleasure, are emerging as fundamental regulators of eating behavior and energy balance.
Serotonin (5-HT), first discovered in 1937 by Vittorio Erspamer and isolated in 1948, is a neurotransmitter that performs multiple functions in the body, from mood regulation to body temperature control, from modulating circadian rhythm to appetite control 1 .
The link between serotonin and obesity is multidimensional and involves multiple pathways, including insulin resistance, high-fat diets, gut microbiota, low-grade inflammation, and interference with tryptophan metabolism 2 .
Central serotonin affects appetite mainly through 5-HT2C receptors, activating anorexigenic neurons such as those producing α-melanocyte-stimulating hormone (α-MSH) and inhibiting orexigenic neurons such as those producing neuropeptide Y (NPY) and agouti-related peptide (AgRP) 2 .
If serotonin represents the dietary "brake," dopamine can be considered the "accelerator" of the reward system. This neurotransmitter is fundamental in modulating the pleasure associated with food consumption and in the motivational processes that drive the search for appetizing foods.
Alterations in the dopaminergic system have been implicated in compulsive eating behaviors and difficulty resisting hyperpalatable food, characteristic of the modern diet.
Dopamine follows closely and reacts to whether the current offer is better or worse than the previous one, while serotonin seems to focus exclusively on the current value of the specific offer under examination 3 .
| Neurotransmitter | Main Functions | Mechanism of Action | Effect on Eating Behavior |
|---|---|---|---|
| Serotonin (5-HT) | Mood regulation, satiety, intestinal motility | Activation of 5-HT2C receptors | Increases feeling of fullness, reduces food intake |
| Dopamine | Reward, motivation, pleasure | Activation of mesolimbic pathway | Modulates food pleasure, reinforces food-seeking behaviors |
This drug acts at the central nervous system level by inhibiting the reuptake of norepinephrine, serotonin, and to a lesser extent, dopamine 4 . Rather than improving mood, sibutramine acts as an anorectic drug, facilitating the appearance of the natural postprandial feeling of satiety and increasing basal metabolism through hyperactivation of the sympathetic system 4 .
Six-month studies demonstrated that sibutramine, at dosages of 30 mg/day, produced weight loss equal to 7.7% compared to initial weight, in addition to reducing triglycerides, total cholesterol, VLDL, C-peptide, and uric acid 4 .
Orlistat represents a different approach, acting peripherally rather than centrally. This drug reduces fat absorption by binding to pancreatic lipases and partially inhibiting the hydrolysis of dietary triglycerides. A meta-analysis of 22 studies showed that orlistat associated with a hypocaloric diet determined an average weight loss of 2.89 kg more than placebo 6 .
Rimonabant was a selective antagonist of type 1 cannabinoid receptors, which acted by reducing the hyperactivation of the endocannabinoid system associated with obesity. In the RIO (Rimonabant In Obesity) program studies, treatment with 20 mg of rimonabant produced a significant reduction in body weight of approximately 6.3-6.9 kg in non-diabetics compared to placebo 6 .
A pioneering study conducted at the Icahn School of Medicine at Mount Sinai provided unprecedented information on the real-time dynamics of dopamine and serotonin during social interaction 3 .
The research, published in Nature Human Behavior, was conducted on four patients with Parkinson's disease undergoing awake neurosurgery at Mount Sinai West in New York City.
During surgery, participants played an ultimatum game, where they had to accept or reject monetary offers of various levels of fairness from both human players and computers. Simultaneously, researchers measured neurotransmitter levels in the substantia nigra, a deep brain region associated with motor control and reward processing 3 .
The revolutionary technique used in this study was voltammetry, developed in collaboration with a team from Virginia Tech. This innovative approach allowed rapid reading of neurochemicals from an electrode positioned deep in the patients' brains during awake brain surgery.
The raw data collected was processed through machine learning tools capable of decoding neurotransmitter levels based on their electrical signatures in the brain 3 .
| Variable | Dopamine Response | Serotonin Response |
|---|---|---|
| Human vs computer interaction | Higher levels with humans | No significant difference |
| Current vs previous offer | Reacts to comparison | No reaction to comparison |
| Current offer value | Reacts to absolute value | Reacts to absolute value |
| Response time | Rapid reaction to changes | More stable reaction over time |
The most promising drugs in the field of obesity therapy are currently GLP-1 receptor agonists such as semaglutide and tirzepatide (which acts on both GLP-1 and GIP) .
These drugs act on multiple neuroendocrine pathways that regulate appetite, satiety, and eating behavior. Unlike purely restrictive approaches, these drugs appear to act on the deep neurological mechanisms that influence eating behavior, reducing the drive toward food and promoting an earlier perception of satiety .
Patients treated with these drugs often report a feeling of "normality" in their eating behaviors, an experience they had never experienced before after years of restrictive diets .
Transcranial Magnetic Stimulation (TMS) is emerging as a promising non-invasive treatment for obesity, especially for those patients who do not respond to conventional therapies or cannot take medications 5 .
This technique uses electromagnetic induction to elicit localized electric currents within the brain, thus modulating neuronal activity 5 .
A 2018 randomized controlled trial demonstrated that after two weeks of treatment with 10 Hz rTMS targeting the left dorsolateral prefrontal cortex (dlPFC), participants showed significant weight loss, reductions in BMI, visceral fat, and caloric intake 5 .
| Technique | Operating Principle | Applications | Advantages |
|---|---|---|---|
| Voltammetry | Real-time electrochemical measurement | Dopamine/serotonin monitoring during tasks | High temporal resolution, direct measurement |
| fMRI | Detection of changes in cerebral blood flow | Identification of activated neural circuits | Non-invasive, broad brain coverage |
| TMS | Modulation of neural activity via magnetic fields | Neuromodulatory therapy, causality studies | Non-invasive, therapeutic potential |
| Animal Models | Genetic manipulation of specific pathways | Study of molecular mechanisms | Experimental control, precise manipulations |
Future research will need to focus on integrating these different therapeutic modalities into multimodal approaches personalized based on the neurobiological, genetic, and psychobehavioral characteristics of each individual with obesity.
The path toward truly effective and personalized therapies for obesity passes through the continued exploration of the fascinating neurochemical dialogue that takes place in our brain every time we open the refrigerator, order at a restaurant, or taste our favorite dish.
Understanding the role of serotonin and dopamine neurotransmitters in regulating eating behavior is revolutionizing our approach to preventing and treating obesity.
We have moved beyond the simplistic model of "eat less, move more" to embrace a more sophisticated vision that recognizes the neurobiological complexity of eating behaviors.
The most advanced research, such as the study conducted by Mount Sinai, is helping us decipher the neurochemical code that regulates our food decisions and our sense of satiety 3 . This knowledge is fueling the development of increasingly targeted therapies ranging from GLP-1 agonist drugs to neuromodulation techniques such as TMS 5 , offering new hope for a health problem that afflicts millions of people worldwide.
We are at the dawn of a new era in obesity treatment, an era in which the precise modulation of neurotransmitters and brain circuits that regulate eating behavior could finally offer millions of people a way out of a condition that for too long has been considered exclusively the fault of individual will.